US2003229082A1PendingUtilityA1
Inhibition of RNA function
Est. expiryJan 16, 2022(expired)· nominal 20-yr term from priority
Inventors:Thomas L. JamesKenneth Egnard LindZhihua DuB. Matija PeterlinKoh FujinagaRodney Kiplin GuyPeter MadridMoriz Mayer
C07D 231/12C07D 233/56A61K 31/4015A61K 31/498A61K 31/343A61K 31/4745A61K 31/475C07D 279/28A61K 31/402A61K 31/538A61K 31/5415C07D 279/06C07D 249/08Y02A50/30A61K 31/542C07D 417/06
35
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Claims
Abstract
Inhibition of RNA function, and treatment or control of diseases or conditions, e.g. infectious diseases such as viruses and viral infections (including HIV) and microbial infections, by the contacting of the RNA with a compound having a central or core structure comprising three fused rings containing from 12 to 15 ring atoms, the central ring including at least one heteroatom selected from nitrogen, oxygen and sulfur, the atoms of the three-ring core structure being optionally substituted with substituents such as halogens, cyano, and/or various substituted or unsubstituted aliphatic and/or heteroaliphatic moieties, or contacting the RNA with yohimbine, usnic acid or N-{4-[2,5-Dioxo-1-(4-trifluoromethoxy-phenyl)-pyrrolidin-3-yl]-phenyl}-2,2,2-trifluoro-acetamide. Preferred compounds are various phenothiazines, including both known and novel compounds.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A method for inhibition of RNA function comprising contacting an RNA molecule with a pharmacologically effective inhibitory amount of
(a) a compound having the formula (I): in which:
A is O; NR 1 ; S(O) n where n is 0, 1 or 2; CR 2 R 3 ; or —A′—CR 4 R 5 where A′ is O, NR 1 , S(O) n wherein n is 0, 1 or 2 or CR 6 R 7 , wherein R 1 through R 7 are independently hydrogen or optionally substituted aliphatic or heteroaliphatic groups;
B is N—R, O, S or CR 8 R 9 in which R is hydrogen or an optionally substituted aliphatic or heteroaliphatic group and R 8 and R 9 are independently hydrogen or optionally substituted aliphatic or heteroaliphatic groups; or when B is N—R, then R, the nitrogen atom of B, and two carbon atoms on the ring adjacent to the nitrogen atom together comprise a ring having the formula —N—C═C—C(OH)═C(COCH 3 )—C(O)—;
provided that at least one of A and B comprises an oxygen, sulfur or nitrogen ring atom;
D and E, together with the carbon atoms to which they are bonded, independently comprise optionally substituted rings of 5-7 atoms selected from C, N, S and O, wherein each ring includes at least one double bond;
and pharmaceutically acceptable salts thereof;
(b) yohimbine; (c) usnic acid; or (d) N-{4-[2,5-Dioxo-1-(4-trifluoromethoxy-phenyl)-pyrrolidin-3-yl]-phenyl}-2,2,2-trifluoro-acetamide.
2 . A method according to claim 1 . in which the compound is of formula (I).
3 . A method according to claim 2 in which D and E are unsubstituted rings.
4 . A method according to claim 2 in which one of D and E is a mono-substituted ring.
5 . A method according to claim 4 in which in which one of D and E is substituted by halogen, trifluoromethyl, cyano, C 1 -C 4 alkoxy or acetyl.
6 . A method according to claim 2 in which D and E are both mono-substituted rings.
7 . A method according to claim 1 . in which the compound has the formula (II)
in which
R is hydrogen or an optionally substituted aliphatic, heteroaliphatic or cycloheteroaliphatic group, or in which the nitrogen atom, R, and two carbon atoms on the ring adjacent to the nitrogen atom, together comprise a ring having the formula —N—C═C—C(OH)═C(COCH 3 )—C(O)—;
and in which carbon atoms on the side rings of the compound are optionally substituted by one or more of —OR′, ═O, ═S, ═NR′, ═N—OR′, —SR′, -halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO 2 R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O) 2 R′, —NR—C(NRR′R″)═NR′″, —R′C(NR′R″)═NR′″, —NR—C(NR′R″)═NR′″, —S(O)R′, —S(O) 2 R′, —S(O) 2 NR′R″, —NRSO 2 R′, —CN and/or —NO 2 , in which R′, R″ and R′″ are each independently selected from hydrogen, halogen, acyl, optionally substituted heteroaliphatic groups, unsubstituted aryl, aryl substituted with 1-3 halogens, optionally substituted aliphatic, optionally substituted oxyaliphatic groups, optionally substituted thioaliphatic groups, or aryl- (C 1 -C 4 )aliphatic groups.;
and pharmaceutically acceptable salts thereof.
8 . A method according to claim 7 in which both side rings are unsubstituted rings.
9 . A method according to claim 7 in which one or both of the side rings is a mono-substituted ring.
10 . A method according to claim 9 in which in which one of the side rings is substituted by halogen, trifluoromethyl, cyano, C 1 -C 4 alkoxy or acetyl.
11 . A method according to claim 7 in which the side rings are both mono-substituted rings.
12 . A method according to claim 7 in which the side rings are either unsubstituted or are substituted at the 2-position by halogen, trifluoromethyl, thiomethyl, acetyl, C 1 -C 4 alkoxy or cyano, and in which R is
(a) a C 2 -C 4 alkylene group substituted by a mono- or dialkylamino group or by an optionally substituted cycloheteroaliphatic group;
(b) an optionally substituted C 2 -C 4 unsaturated acyclic aliphatic group, or
(c) a C 2 -C 4 acyl group substituted by a mono- or dialkylamino group.
13 . A method according to claim 7 in which the compound is acetylpromazine, chlorpromazine, prochlorperazine, promazine, or trifluoperazine.
14 . A method according to claim 2 . in which the compound has the formula (III):
in which R is (CH 2 ) 3 R 12 ; R 10 is halogen or C 1 -C 4 alkoxy; R 11 is hydrogen if R 10 is halogen and is hydrogen or methyl if R 10 is alkoxy; and R 12 is selected from —N(CH 2 CH 2 )OH, —N(n-C 4 H 9 ), —N(CH 2 C 6 H 5 ),
if R 10 is halogen, and is —N(CH 3 ) 2 if R 10 is alkoxy.
15 . A method according to claim 1 . in which the compound is yohimbine.
16 . A method according to claim 1 . in which the compound is usnic acid.
17 . A method according to claim 1 . in which the compound is N-{4-[2,5-Dioxo-1-(4-trifluoromethoxy-phenyl)-pyrrolidin-3-yl]-phenyl}-2,2,2-trifluoro-acetamide.
18 . A method according to claim 1 . in which the compound is a phenothiazine.
19 . A method according to claim 1 . in which the compound is a thioxanthene.
20 . A method according to claim 1 . in which the compound is a thianthrene.
21 . A method according to claim 1 . in which the compound is a phenoxazine.
22 . A method according to claim 1 . in which the compound is a phenazine.
23 . A method according to claim 1 . in which the compound is a phenoxathiin.
24 . A method according to claim 1 . in which the compound is a benzepine.
25 . A method according to claim 1 . in which the RNA is viral or microbial RNA.
26 . A method according to claim 1 . in which the RNA is viral RNA.
27 . A method according to claim 1 . in which the RNA is retroviral RNA.
28 . A method according to claim 1 . in which the RNA is HIV RNA.
29 . A method according to claim 18 in which the compound inhibits RNA function by binding to the TAR site.
30 . A method according to claim 1 . in which the RNA is microbial RNA
31 . A method according to claim 28 in which the RNA is bacterial RNA.
32 . A method according to claim 28 in which the RNA is fungal RNA
33 . A method according to claim 28 in which the RNA is protozoal RNA.
34 . A method for inhibition of RNA function comprising contacting cells comprising RNA with a pharmacologically effective inhibitory amount of
(a) a compound having the formula (I): in which:
A is O; NR 1 ; S(O) n where n is 0, 1 or 2; CR 2 R 3 ; or —A′—CR 4 R 5 where A′ is O, NR 1 , S(O) n wherein n is 0, 1 or 2 or CR 6 R 7 , wherein R 1 through R 7 are independently hydrogen or optionally substituted aliphatic or heteroaliphatic groups;
B is N—R, O, S or CR 8 R 9 in which R is hydrogen or an optionally substituted aliphatic or heteroaliphatic group and R 8 and R 9 are independently hydrogen or optionally substituted aliphatic or heteroaliphatic groups; or when B is N—R, then R, the nitrogen atom of B, and two carbon atoms on the ring adjacent to the nitrogen atom together comprise a ring having the formula —N—C═C—C(OH)═C(COCH 3 )—C(O)—;
provided that at least one of A and B comprises an oxygen, sulfur or nitrogen ring atom;
D and E, together with the carbon atoms to which they are bonded, independently comprise optionally substituted rings of 5-7 atoms selected from C, N, S and O, wherein each ring includes at least one double bond;
and pharmaceutically acceptable salts thereof;
(b) yohimbine; (c) usnic acid; or (d) N-{4-[2,5-Dioxo-1-(4-trifluoromethoxy-phenyl)-pyrrolidin-3-yl]-phenyl}-2,2,2-trifluoro-acetamide.
35 . A method according to claim 34 in which the compound is of formula (I).
36 . A method according to claim 35 in which D and E are unsubstituted rings.
37 . A method according to claim 36 in which one of D and E is a mono-substituted ring.
38 . A method according to claim 37 in which in which one of D and E is substituted by halogen, trifluoromethyl, cyano, C 1 -C 4 alkoxy or acetyl.
39 . A method according to claim 35 in which D and E are both mono-substituted rings.
40 . A method according to claim 34 in which the compound has the formula (II)
in which
R is hydrogen or an optionally substituted aliphatic, heteroaliphatic or cycloheteroaliphatic group, or in which the nitrogen atom, R, and two carbon atoms on the ring adjacent to the nitrogen atom, together comprise a ring having the formula —N—C═C—C(OH)═C(COCH 3 )—C(O)—;
and in which carbon atoms on the side rings of the compound are optionally substituted by one or more of —OR′, ═O, ═S, ═NR′, ═N—OR′, —NR′R″, —SR′, -halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO 2 R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O) 2 R′, —NR—C(NRR′R″)═NR′″, —R′C(NR′R″)═NR′″, —NR—C(NR′R″)═NR′″, —S(O)R′, —S(O) 2 R′, —S(O) 2 NR′R″, —NRSO 2 R′, —CN and/or —NO 2 , in which R′, R″ and R′″ are each independently selected from hydrogen, halogen, acyl, optionally substituted heteroaliphatic groups, unsubstituted aryl, aryl substituted with 1-3 halogens, optionally substituted aliphatic, optionally substituted oxyaliphatic groups, optionally substituted thioaliphatic groups, or aryl- (C 1 -C 4 )aliphatic groups.;
and pharmaceutically acceptable salts thereof.
41 . A method according to claim 40 in which both side rings are unsubstituted rings.
42 . A method according to claim 40 in which one or both of the side rings is a mono-substituted ring.
43 . A method according to claim 42 in which in which one of the side rings is substituted by halogen, trifluoromethyl, cyano, C 1 -C 4 alkoxy or acetyl.
44 . A method according to claim 40 in which the side rings are both mono-substituted rings.
45 . A method according to claim 40 in which the side rings are either unsubstituted or are substituted at the 2-position by halogen, trifluoromethyl, thiomethyl, acetyl, C 1 -C 4 alkoxy or cyano, and in which R is
(a) a C 2 -C 4 alkylene group substituted by a mono- or dialkylamino group or by an optionally substituted cycloheteroaliphatic group;
(b) an optionally substituted C 2 -C 4 unsaturated acyclic aliphatic group, or
(c) a C 2 -C 4 acyl group substituted by a mono- or dialkylamino group.
46 . A method according to claim 40 in which the compound is acetylpromazine, chlorpromazine, prochlorperazine, promazine, or trifluoperazine.
47 . A method according to claim 35 in which the compound has the formula (III):
in which R is (CH 2 ) 3 R 12 ; R 10 is halogen or C 1 -C 4 alkoxy; R 11 is hydrogen if R 10 is halogen and is hydrogen or methyl if R 10 is alkoxy; and R 12 is selected from —N(CH 2 CH 2 )OH, —N(n-C 4 H 9 ), —N(CH 2 C 6 H 5 ),
if R 10 is halogen, and is —N(CH 3 ) 2 if R 10 is alkoxy.
48 . A method according to claim 34 in which the compound is yohimbine.
49 . A method according to claim 34 in which the compound is usnic acid.
50 . A method according to claim 34 in which the compound is N-{4-[2,5-Dioxo-1-(4-trifluoromethoxy-phenyl)-pyrrolidin-3-yl]-phenyl}-2,2,2-trifluoro-acetamide.
51 . A method according to claim 34 in which the compound is a phenothiazine.
52 . A method according to claim 34 in which the compound is a thioxanthene.
53 . A method according to claim 34 in which the compound is a thianthrene.
54 . A method according to claim 34 in which the compound is a phenoxazine.
55 . A method according to claim 34 in which the compound is a phenazine.
56 . A method according to claim 34 in which the compound is a phenoxathiin.
57 . A method according to claim 34 in which the compound is a benzepine.
58 . A method for inhibition of microbial infection in a subject comprising administering to said subject a pharmacologically effective inhibitory amount of
(a) a compound having the formula (I): in which:
A is O; NR 1 ; S(O) n where n is 0, 1 or 2; CR 2 R 3 ; or —A′—CR 4 R 5 where A′ is O, NR 1 , S(O) n wherein n is 0, 1 or 2 or CR 6 R 7 , wherein R 1 through R 7 are independently hydrogen or optionally substituted aliphatic or heteroaliphatic groups;
B is N—R, O, S or CR 8 R 9 in which R is hydrogen or an optionally substituted aliphatic or heteroaliphatic group and R 8 and R 9 are independently hydrogen or optionally substituted aliphatic or heteroaliphatic groups; or when B is N—R, then R, the nitrogen atom of B, and two carbon atoms on the ring adjacent to the nitrogen atom together comprise a ring having the formula —N—C═C—C(OH)═C(COCH 3 )—C(O)—;
provided that at least one of A and B comprises an oxygen, sulfur or nitrogen ring atom;
D and E, together with the carbon atoms to which they are bonded, independently comprise optionally substituted rings of 5-7 atoms selected from C, N, S and O, wherein each ring includes at least one double bond;
and pharmaceutically acceptable salts thereof;
(b) yohimbine; (c) usnic acid; or (d) N-{4-[2,5-Dioxo-1-(4-trifluoromethoxy-phenyl)-pyrrolidin-3-yl]-phenyl}-2,2,2-trifluoro-acetamide.
59 . A method according to claim 58 in which the compound is of formula (I).
60 . A method according to claim 59 in which D and E are unsubstituted rings.
61 . A method according to claim 59 in which one of D and E is a mono-substituted ring.
62 . A method according to claim 62 in which in which one of D and E is substituted by halogen, trifluoromethyl, cyano, C 1 -C 4 alkoxy or acetyl.
63 . A method according to claim 59 in which D and E are both mono-substituted rings.
64 . A method according to claim 58 in which the compound has the formula (II)
in which
R is hydrogen or an optionally substituted aliphatic, heteroaliphatic or cycloheteroaliphatic group, or in which the nitrogen atom, R, and two carbon atoms on the ring adjacent to the nitrogen atom, together comprise a ring having the formula —N—C═C—C(OH)═C(COCH 3 )—C(O)—;
and in which carbon atoms on the side rings of the compound are optionally substituted by one or more of —OR′, ═O, ═S, ═NR′, ═N—OR′, —NR′R″, —SR′, -halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO 2 R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O) 2 R′, —NR—C(NRR′R″)═NR′″, —R′C(NR′R″)═NR′″, —NR—C(NR′R″)═NR′″, —S(O)R′, —S(O) 2 R′, —S(O) 2 NR′R″, —NRSO 2 R′, —CN and/or —NO 2 , in which R′, R″ and R′″ are each independently selected from hydrogen, halogen, acyl, optionally substituted heteroaliphatic groups, unsubstituted aryl, aryl substituted with 1-3 halogens, optionally substituted aliphatic, optionally substituted oxyaliphatic groups, optionally substituted thioaliphatic groups, or aryl- (C 1 -C 4 )aliphatic groups.;
and pharmaceutically acceptable salts thereof.
65 . A method according to claim 64 in which both side rings are unsubstituted rings.
66 . A method according to claim 64 in which one or both of the side rings is a mono-substituted ring.
67 . A method according to claim 66 in which one of the side rings is substituted by halogen, trifluoromethyl, cyano, C 1 -C 4 alkoxy or acetyl.
68 . A method according to claim 64 in which the side rings are both mono-substituted rings.
69 . A method according to claim 64 in which the side rings are either unsubstituted or are substituted at the 2-position by halogen, trifluoromethyl, thiomethyl, acetyl, C 1 -C 4 alkoxy or cyano, and in which R is
(a) a C 2 -C 4 alkylene group substituted by a mono- or dialkylamino group or by an optionally substituted cycloheteroaliphatic group;
(b) an optionally substituted C 2 -C 4 unsaturated acyclic aliphatic group, or
(c) a C 2 -C 4 acyl group substituted by a mono- or dialkylamino group.
70 . A method according to claim 64 in which the compound is acetylpromazine, chlorpromazine, prochlorperazine, promazine, or trifluoperazine.
71 . A method according to claim 59 in which the compound has the formula (III):
in which R is (CH 2 ) 3 R 12 ; R 10 is halogen or C 1 -C 4 alkoxy; R 11 is hydrogen if R 10 is halogen and is hydrogen or methyl if R 10 is alkoxy; and R 12 is selected from —N(CH 2 CH 2 )OH, —N(n-C 4 H 9 ), —N(CH 2 C 6 H 5 ),
if R 10 is halogen, and is —N(CH 3 ) 2 if R 10 is alkoxy.
72 . A method according to claim 58 in which the compound is yohimbine.
73 . A method according to claim 58 in which the compound is usnic acid.
74 . A method according to claim 58 in which the compound is N-{4-[2,5-Dioxo-1-(4-trifluoromethoxy-phenyl)-pyrrolidin-3-yl]-phenyl}-2,2,2-trifluoro-acetamide.
75 . A method according to claim 58 in which the compound is a phenothiazine.
76 . A method according to claim 58 in which the compound is a thioxanthene.
77 . A method according to claim 58 in which the compound is a thianthrene.
78 . A method according to claim 58 in which the compound is a phenoxazine.
79 . A method according to claim 58 in which the compound is a phenazine.
80 . A method according to claim 58 in which the compound is a phenoxathiin.
81 . A method according to claim 58 in which the compound is a benzepine.
82 . A method according to claim 65 in which the infection is a bacterial infection.
83 . A method for inhibiting a viral infection in a subject comprising administering to said subject a pharmacologically effective inhibitory amount of
(a) a compound having the formula (I): in which:
A is O; NR 1 ; S(O) n where n is 0, 1 or 2; CR 2 R 3 ; or —A′—CR 4 R 5 where A′ is O, NR 1 , S(O) n wherein n is 0, 1 or 2 or CR 6 R 7 , wherein R 1 through R 7 are independently hydrogen or optionally substituted aliphatic or heteroaliphatic groups;
B is N—R, O, S or CR 8 R 9 in which R is hydrogen or an optionally substituted aliphatic or heteroaliphatic group and R 8 and R 9 are independently hydrogen or optionally substituted aliphatic or heteroaliphatic groups; or when B is N—R, then R, the nitrogen atom of B, and two carbon atoms on the ring adjacent to the nitrogen atom together comprise a ring having the formula —N—C═C—C(OH)═C(COCH 3 )—C(O)—;
provided that at least one of A and B comprises an oxygen, sulfur or nitrogen ring atom;
D and E, together with the carbon atoms to which they are bonded, independently comprise optionally substituted rings of 5-7 atoms selected from C, N, S and O, wherein each ring includes at least one double bond;
and pharmaceutically acceptable salts thereof;
(b) yohimbine; (c) usnic acid; or (d) N-{4-[2,5-Dioxo-1-(4-trifluoromethoxy-phenyl)-pyrrolidin-3-yl]-phenyl}-2,2,2-trifluoro-acetamide.
84 . A method according to claim 83 in which the compound is of formula (I).
85 . A method according to claim 84 . in which D and E are unsubstituted rings.
86 . A method according to claim 84 . in which one of D and E is a mono-substituted ring.
87 . A method according to claim 86 in which in which one of D and E is substituted by halogen, trifluoromethyl, cyano, C 1 -C 4 alkoxy or acetyl.
88 . A method according to claim 84 in which D and E are both mono-substituted rings.
89 . A method according to claim 83 in which the compound has the formula (II)
in which
R is hydrogen or an optionally substituted aliphatic, heteroaliphatic or cycloheteroaliphatic group, or in which the nitrogen atom, R, and two carbon atoms on the ring adjacent to the nitrogen atom, together comprise a ring having the formula —N—C═C—C(OH)═C(COCH 3 )—C(O)—;
and in which carbon atoms on the side rings of the compound are optionally substituted by one or more of —OR′, ═O, ═S, ═NR′, ═N—OR′, —NR′R″, —SR′, -halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO 2 R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O) 2 R′, —NR—C(NRR′R″)═NR′″, —R′C(NR′R″)═NR′″, —NR—C(NR′R″)═NR′″, —S(O)R′, —S(O) 2 R′, —S(O) 2 NR′R″, —NRSO 2 R′, —CN and/or —NO 2 , in which R′, R″ and R′″ are each independently selected from hydrogen, halogen, acyl, optionally substituted heteroaliphatic groups, unsubstituted aryl, aryl substituted with 1-3 halogens, optionally substituted aliphatic, optionally substituted oxyaliphatic groups, optionally substituted thioaliphatic groups, or aryl- (C 1 -C 4 )aliphatic groups.;
and pharmaceutically acceptable salts thereof.
90 . A method according to claim 89 in which both side rings are unsubstituted rings.
91 . A method according to claim 89 in which one or both of the side rings is a mono-substituted ring.
92 . A method according to claim 91 in which in which one of the side rings is substituted by halogen, trifluoromethyl, cyano, C 1 -C 4 alkoxy or acetyl.
93 . A method according to claim 89 in which the side rings are both mono-substituted rings.
94 . A method according to claim 89 in which the side rings are either unsubstituted or are substituted at the 2-position by halogen, trifluoromethyl, thiomethyl, acetyl, C 1 -C 4 alkoxy or cyano, and in which R is
(a) a C 2 -C 4 alkylene group substituted by a mono- or dialkylamino group or by an optionally substituted cycloheteroaliphatic group;
(b) an optionally substituted C 2 -C 4 unsaturated acyclic aliphatic group, or
(c) a C 2 -C 4 acyl group substituted by a mono- or dialkylamino group.
95 . A method according to claim 89 in which the compound is acetylpromazine, chlorpromazine, prochlorperazine, promazine, or trifluoperazine.
96 . A method according to claim 84 in which the compound has the formula (III):
in which R is (CH 2 ) 3 R 12 ; R 10 is halogen or C 1 -C 4 alkoxy; R 11 is hydrogen if R 10 is halogen and is hydrogen or methyl if R 10 is alkoxy; and R 12 is selected from —N(CH 2 CH 2 )OH, —N(n-C 4 H 9 ), —N(CH 2 C 6 H 5 ),
if R 10 is halogen, and is —N(CH 3 ) 2 if R 10 is alkoxy.
97 . A method according to claim 83 in which the compound is yohimbine.
98 . A method according to claim 83 in which the compound is usnic acid.
99 . A method according to claim 83 in which the compound is N-{4-[2,5-Dioxo-1-(4-trifluoromethoxy-phenyl)-pyrrolidin-3-yl]-phenyl}-2,2,2-trifluoro-acetamide.
100 . A method according to claim 83 in which the compound is a phenothiazine.
101 . A method according to claim 83 in which the compound is a thioxanthene.
102 . A method according to claim 83 in which the compound is a thianthrene.
103 . A method according to claim 83 in which the compound is a phenoxazine.
104 . A method according to claim 83 in which the compound is a phenazine.
105 . A method according to claim 83 in which the compound is a phenoxathiin.
106 . A method according to claim 83 in which the compound is a benzepine.
107 . A method according to claim 110 wherein the viral infection comprises a retroviral infection.
108 . A method according to claim 110 wherein the viral infection comprises AIDS.
109 . A method according to claim 110 wherein the viral infection comprises a polio viral infection.
110 . A method according to claim 110 wherein the viral infection comprises a rhinoviral infection.
111 . A method according to claim 34 wherein the viral infection comprises an enteroviral infection.
112 . A method according to claim 34 wherein the viral infection comprises hepatitis C.
113 . A method for inhibition of viral RNA function comprising administering to a subject a pharmacologically effective inhibitory amount of
(a) a compound having the formula (I): in which:
A is O; NR 1 ; S(O) n where n is 0, 1 or 2; CR 2 R 3 ; or —A′—CR 4 R 5 where A′ is O, NR 1 , S(O) n wherein n is 0, 1 or 2 or CR 6 R 7 , wherein R 1 through R 7 are independently hydrogen or optionally substituted aliphatic or heteroaliphatic groups;
B is N—R, O, S or CR 8 R 9 in which R is hydrogen or an optionally substituted aliphatic or heteroaliphatic group and R 8 and R 9 are independently hydrogen or optionally substituted aliphatic or heteroaliphatic groups; or when B is N—R, then R, the nitrogen atom of B, and two carbon atoms on the ring adjacent to the nitrogen atom together comprise a ring having the formula —N—C═C—C(OH)═C(COCH 3 )—C(O)—;
provided that at least one of A and B comprises an oxygen, sulfur or nitrogen ring atom;
D and E, together with the carbon atoms to which they are bonded, independently comprise optionally substituted rings of 5-7 atoms selected from C, N, S and O, wherein each ring includes at least one double bond;
and pharmaceutically acceptable salts thereof;
(b) yohimbine; (c) usnic acid; or (d) N-{4-[2,5-Dioxo-1-(4-trifluoromethoxy-phenyl)-pyrrolidin-3-yl]-phenyl}-2,2,2-trifluoro-acetamide.
114 . A method according to claim 113 in which the compound is of formula (I).
115 . A method according to claim 114 in which D and E are unsubstituted rings.
116 . A method according to claim 114 in which one of D and E is a mono-substituted ring.
117 . A method according to claim 116 in which in which one of D and E is substituted by halogen, trifluoromethyl, cyano, C 1 -C 4 alkoxy or acetyl.
118 . A method according to claim 114 in which D and E are both mono-substituted rings.
119 . A method according to claim 113 in which the compound has the formula (II)
in which
R is hydrogen or an optionally substituted aliphatic, heteroaliphatic or cycloheteroaliphatic group, or in which the nitrogen atom, R, and two carbon atoms on the ring adjacent to the nitrogen atom, together comprise a ring having the formula —N—C═C—C(OH)═C(COCH 3 )—C(O)—;
and in which carbon atoms on the side rings of the compound are optionally substituted by one or more of —OR′, ═O, ═S, ═NR′, ═N—OR′, —NR′R″, —SR′, -halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO 2 R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O) 2 R′, —NR—C(NRR′R″)═NR′″, —R′C(NR′R″)═NR′″, —NR—C(NR′R″)═NR′″, —S(O)R′, —S(O) 2 R′, —S(O) 2 NR′R″, —NRSO 2 R′, —CN and/or —NO 2 , in which R′, R″ and R′″ are each independently selected from hydrogen, halogen, acyl, optionally substituted heteroaliphatic groups, unsubstituted aryl, aryl substituted with 1-3 halogens, optionally substituted aliphatic, optionally substituted oxyaliphatic groups, optionally substituted thioaliphatic groups, or aryl- (C 1 -C 4 )aliphatic groups.;
and pharmaceutically acceptable salts thereof.
120 . A method according to claim 119 in which both side rings are unsubstituted rings.
121 . A method according to claim 119 in which one or both of the side rings is a mono-substituted ring.
122 . A method according to claim 119 in which one of the side rings is substituted by halogen, trifluoromethyl, cyano, C 1 -C 4 alkoxy or acetyl.
123 . A method according to claim 119 in which the side rings are both mono-substituted rings.
124 . A method according to claim 119 in which the side rings are either unsubstituted or are substituted at the 2-position by halogen, trifluoromethyl, thiomethyl, acetyl, C 1 -C 4 alkoxy or cyano, and in which R is
(a) a C 2 -C 4 alkylene group substituted by a mono- or dialkylamino group or by an optionally substituted cycloheteroaliphatic group;
(b) an optionally substituted C 2 -C 4 unsaturated acyclic aliphatic group, or
(c) a C 2 -C 4 acyl group substituted by a mono- or dialkylamino group.
125 . A method according to claim 119 in which the compound is acetylpromazine, chlorpromazine, prochlorperazine, promazine, or trifluoperazine.
126 . A method according to claim 114 in which the compound has the formula (III):
in which R is (CH 2 ) 3 R 12 ; R 10 is halogen or C 1 -C 4 alkoxy; R 11 is hydrogen if R 10 is halogen and is hydrogen or methyl if R 10 is alkoxy; and R 12 is selected from —N(CH 2 CH 2 )OH, —N(n-C 4 H 9 ), —N(CH 2 C 6 H 5 ),
if R 10 is halogen, and is —N(CH 3 ) 2 if R 10 is alkoxy.
127 . A method according to claim 113 in which the compound is yohimbine.
128 . A method according to claim 113 in which the compound is usnic acid.
129 . A method according to claim 113 in which the compound is N-{4-[2,5-Dioxo-1-(4-trifluoromethoxy-phenyl)-pyrrolidin-3-yl]-phenyl}-2,2,2-trifluoro-acetamide.
130 . A method according to claim 113 in which the compound is a phenothiazine.
131 . A method according to claim 113 in which the compound is a thioxanthene.
132 . A method according to claim 113 in which the compound is a thianthrene.
133 . A method according to claim 113 in which the compound is a phenoxazine.
134 . A method according to claim 113 in which the compound is a phenazine.
135 . A method according to claim 113 in which the compound is a phenoxathiin.
136 . A method according to claim 113 in which the compound is a benzepine.
137 . A method for inhibition of microbial RNA function comprising administering to a subject a pharmacologically effective inhibitory amount of
(a) a compound having the formula (I): in which:
A is O; NR 1 ; S(O) n where n is 0, 1 or 2; CR 2 R 3 ; or —A′—CR 4 R 5 where A′ is O, NR 1 , S(O) n wherein n is 0, 1 or 2 or CR 6 R 7 , wherein R 1 through R 7 are independently hydrogen or optionally substituted aliphatic or heteroaliphatic groups;
B is N—R, O, S or CR 8 R 9 in which R is hydrogen or an optionally substituted aliphatic or heteroaliphatic group and R 8 and R 9 are independently hydrogen or optionally substituted aliphatic or heteroaliphatic groups; or when B is N—R, then R, the nitrogen atom of B, and two carbon atoms on the ring adjacent to the nitrogen atom together comprise a ring having the formula —N—C═C—C(OH)═C(COCH 3 )—C(O)—;
provided that at least one of A and B comprises an oxygen, sulfur or nitrogen ring atom;
D and E, together with the carbon atoms to which they are bonded, independently comprise optionally substituted rings of 5-7 atoms selected from C, N, S and O, wherein each ring includes at least one double bond;
and pharmaceutically acceptable salts thereof;
(b) yohimbine; (c) usnic acid; or (d) N-{4-[2,5-Dioxo-1-(4-trifluoromethoxy-phenyl)-pyrrolidin-3-yl]-phenyl}-2,2,2-trifluoro-acetamide.
138 . A method according to claim 137 in which the compound is of formula (I).
139 . A method according to claim 138 in which D and E are unsubstituted rings.
140 . A method according to claim 138 in which one of D and E is a mono-substituted ring.
141 . A method according to claim 141 in which in which one of D and E is substituted by halogen, trifluoromethyl, cyano, C 1 -C 4 alkoxy or acetyl.
142 . A method according to claim 138 in which D and E are both mono-substituted rings.
143 . A method according to claim 137 in which the compound has the formula (II)
in which
R is hydrogen or an optionally substituted aliphatic, heteroaliphatic or cycloheteroaliphatic group, or in which the nitrogen atom, R, and two carbon atoms on the ring adjacent to the nitrogen atom, together comprise a ring having the formula —N—C═C—C(OH)═C(COCH 3 )—C(O)—;
and in which carbon atoms on the side rings of the compound are optionally substituted by one or more of —OR′, ═O, ═S, ═NR′, ═N—OR′, —NR′R″, —SR′, -halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO 2 R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O) 2 R′, —NR—C(NRR′R″)═NR′″, —R′C(NR′R″)═NR′″, —NR—C(NR′R″)═NR′″, —S(O)R′, —S(O) 2 R′, —S(O) 2 NR′R″, —NRSO 2 R′, —CN and/or —NO 2 , in which R′, R″ and R′″ are each independently selected from hydrogen, halogen, acyl, optionally substituted heteroaliphatic groups, unsubstituted aryl, aryl substituted with 1-3 halogens, optionally substituted aliphatic, optionally substituted oxyaliphatic groups, optionally substituted thioaliphatic groups, or aryl- (C 1 -C 4 )aliphatic groups.;
and pharmaceutically acceptable salts thereof.
144 . A method according to claim 143 in which both side rings are unsubstituted rings.
145 . A method according to claim 143 in which one or both of the side rings is a mono-substituted ring.
146 . A method according to claim 145 in which one of the side rings is substituted by halogen, trifluoromethyl, cyano, C 1 -C 4 alkoxy or acetyl.
147 . A method according to claim 143 in which the side rings are both mono-substituted rings.
148 . A method according to claim 143 in which in which the side rings are either unsubstituted or are substituted at the 2-position by halogen, trifluoromethyl, thiomethyl, acetyl, C 1 -C 4 alkoxy or cyano, and in which R is
(a) a C 2 -C 4 alkylene group substituted by a mono- or dialkylamino group or by an optionally substituted cycloheteroaliphatic group;
(b) an optionally substituted C 2 -C 4 unsaturated acyclic aliphatic group, or
(c) a C 2 -C 4 acyl group substituted by a mono- or dialkylamino group.
149 . A method according to claim 143 in which the compound is acetylpromazine, chlorpromazine, prochlorperazine, promazine, or trifluoperazine.
150 . A method according to claim 138 in which the compound has the formula (III):
in which R is (CH 2 ) 3 R 12 ; R 10 is halogen or C 1 -C 4 alkoxy; R 11 is hydrogen if R 10 is halogen and is hydrogen or methyl if R 10 is alkoxy; and R 12 is selected from —N(CH 2 CH 2 )OH, —N(n-C 4 H 9 ), —N(CH 2 C 6 H 5 ),
if R 10 is halogen, and is —N(CH 3 ) 2 if R 10 is alkoxy.
151 . A method according to claim 137 in which the compound is yohimbine.
152 . A method according to claim 137 in which the compound is usnic acid.
153 . A method according to claim 137 in which the compound is N-{4-[2,5-Dioxo-1-(4-trifluoromethoxy-phenyl)-pyrrolidin-3-yl]-phenyl}-2,2,2-trifluoro-acetamide.
154 . A method according to claim 137 in which the compound is a phenothiazine.
155 . A method according to claim 137 in which the compound is a thioxanthene.
156 . A method according to claim 137 in which the compound is a thianthrene.
157 . A method according to claim 137 in which the compound is a phenoxazine.
158 . A method according to claim 137 in which the compound is a phenazine.
159 . A method according to claim 137 in which the compound is a phenoxathiin.
160 . A method according to claim 137 in which the compound is a benzepine.
161 . A method according to claim 111 in which the RNA is bacterial RNA.
162 . A method for increasing or decreasing the production of a protein comprising the step of contacting a target messenger RNA molecule that encodes said protein with
(a) a compound having the formula (I): in which:
A is O; NR 1 ; S(O) n where n is 0, 1 or 2; CR 2 R 3 ; or —A′—CR 4 R 5 where A′ is O, NR 1 , S(O) n wherein n is 0, 1 or 2 or CR 6 R 7 , wherein R 1 through R 7 are independently hydrogen or optionally substituted aliphatic or heteroaliphatic groups;
B is N—R, O, S or CR 8 R 9 in which R is hydrogen or an optionally substituted aliphatic or heteroaliphatic group and R 8 and R 9 are independently hydrogen or optionally substituted aliphatic or heteroaliphatic groups; or when B is N—R, then R, the nitrogen atom of B, and two carbon atoms on the ring adjacent to the nitrogen atom together comprise a ring having the formula —N—C═C—C(OH)═C(COCH 3 )—C(O)—;
provided that at least one of A and B comprises an oxygen, sulfur or nitrogen ring atom;
D and E, together with the carbon atoms to which they are bonded, independently comprise optionally substituted rings of 5-7 atoms selected from C, N, S and O, wherein each ring includes at least one double bond;
and pharmaceutically acceptable salts thereof;
(b) yohimbine; (c) usnic acid; or (d) N-{4-[2,5-Dioxo-1-(4-trifluoromethoxy-phenyl)-pyrrolidin-3-yl]-phenyl}-2,2,2-trifluoro-acetamide.
163 . A method according to claim 113 , wherein increasing or decreasing the production of a protein interferes with the progression of a disease associated with decreasing or increasing the production of said protein, respectively.
164 . A method according to claim 114 , wherein the disease is selected from the group consisting of amyloidosis, hemophilia, Alzheimer's disease, atherosclerosis, cancer, giantism, dwarfism, hypothyroidism, hyperthyroidism, inflammation, cystic fibrosis, autoimmune disorders, diabetes, aging, obesity, neurodegenerative disorders, and Parkinson's disease.
165 . A method according to claim 114 , wherein said disease is caused by a bacteria, a fungus, a protozoa, or a virus.
166 . A method according to claim 162 , wherein the disease is selected from the group consisting of HIV infection, AIDS, human T-cell leukemia, SIV infection, FIV infection, feline leukemia, hepatitis A, hepatitis B, hepatitis C, Dengue fever, malaria, rotavirus infection, severe acute gastroenteritis, diarrhea, encephalitis, hemorrhagic fever, syphilis, legionella, whooping cough, gonorrhea, sepsis, influenza, pneumonia, tinea infection, candida infection, and meningitis.
167 . A pharmaceutical composition comprising an amount of
(a) a compound having the formula (I): in which:
A is O; NR 1 ; S(O) n where n is 0, 1 or 2; CR 2 R 3 ; or —A′—CR 4 R 5 where A′ is O, NR 1 , S(O) n wherein n is 0, 1 or 2 or CR 6 R 7 , wherein R 1 through R 7 are independently hydrogen or optionally substituted aliphatic or heteroaliphatic groups;
B is N—R, O, S or CR 8 R 9 in which R is hydrogen or an optionally substituted aliphatic or heteroaliphatic group and R 8 and R 9 are independently hydrogen or optionally substituted aliphatic or heteroaliphatic groups; or when B is N—R, then R, the nitrogen atom of B, and two carbon atoms on the ring adjacent to the nitrogen atom together comprise a ring having the formula —N—C═C—C(OH)═C(COCH 3 )—C(O)—;
provided that at least one of A and B comprises an oxygen, sulfur or nitrogen ring atom;
D and E, together with the carbon atoms to which they are bonded, independently comprise optionally substituted rings of 5-7 atoms selected from C, N, S and O, wherein each ring includes at least one double bond;
and pharmaceutically acceptable salts thereof;
(b) yohimbine; (c) usnic acid; or (d) N-{4-[2,5-Dioxo-1-(4-trifluoromethoxy-phenyl)-pyrrolidin-3-yl]-phenyl}-2,2,2-trifluoro-acetamide,
that is pharmacologically effective to inhibit one or more functions of a viral or microbial RNA.
168 . A composition according to claim 167 in which the compound is of formula (I).
169 . A composition according to claim 168 in which D and E are unsubstituted rings.
170 . A composition according to claim 168 in which one of D and E is a mono-substituted ring.
171 . A composition according to claim 170 in which in which one of D and E is substituted by halogen, trifluoromethyl, cyano, C 1 -C 4 alkoxy or acetyl.
172 . A composition according to claim 168 in which D and E are both mono-substituted rings.
173 . A composition according to claim 167 in which the compound has the formula (II)
in which
R is hydrogen or an optionally substituted aliphatic, heteroaliphatic or cycloheteroaliphatic group, or in which the nitrogen atom, R, and two carbon atoms on the ring adjacent to the nitrogen atom, together comprise a ring having the formula —N—C═C—C(OH)═C(COCH 3 )—C(O)—;
and in which carbon atoms on the side rings of the compound are optionally substituted by one or more of —OR′, ═O, ═S, ═NR′, ═N—OR′, —NR′R″, —SR′, -halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO 2 R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O) 2 R′, —NR—C(NRR′R″)═NR′″, —R′C(NR′R″)═NR′″, —NR—C(NR′R″)═NR′″, —S(O)R′, —S(O) 2 R′, —S(O) 2 NR′R″, —NRSO 2 R′, —CN and/or —NO 2 , in which R′, R″ and R′″ are each independently selected from hydrogen, halogen, acyl, optionally substituted heteroaliphatic groups, unsubstituted aryl, aryl substituted with 1-3 halogens, optionally substituted aliphatic, optionally substituted oxyaliphatic groups, optionally substituted thioaliphatic groups, or aryl- (C 1 -C 4 )aliphatic groups.;
and pharmaceutically acceptable salts thereof.
174 . A composition according to claim 173 in which both side rings are unsubstituted rings.
175 . A composition according to claim 173 in which one or both of the side rings is a mono-substituted ring.
176 . A composition according to claim 175 in which in which one of the side rings is substituted by halogen, trifluoromethyl, cyano, C 1 -C 4 alkoxy or acetyl.
177 . A composition according to claim 173 in which the side rings are both mono-substituted rings.
178 . A composition according to claim 173 in which the side rings are either unsubstituted or are substituted at the 2-position by halogen, trifluoromethyl, thiomethyl, acetyl, C 1 -C 4 alkoxy or cyano, and in which R is
(a) a C 2 -C 4 alkylene group substituted by a mono- or dialkylamino group or by an optionally substituted cycloheteroaliphatic group;
(b) an optionally substituted C 2 -C 4 unsaturated acyclic aliphatic group, or
(c) a C 2 -C 4 acyl group substituted by a mono- or dialkylamino group.
179 . A composition according to claim 173 in which the compound is acetylpromazine, chlorpromazine, prochlorperazine, promazine, or trifluoperazine.
180 . A composition according to claim 168 in which the compound has the formula (III):
in which R is (CH 2 ) 3 R 12 ; R 10 is halogen or C 1 -C 4 alkoxy; R 11 is hydrogen if R 10 is halogen and is hydrogen or methyl if R 10 is alkoxy; and R 12 is selected from —N(CH 2 CH 2 )OH, —N(n-C 4 H 9 ), —N(CH 2 C 6 H 5 ),
if R 10 is halogen, and is —N(CH 3 ) 2 if R 10 is alkoxy.
181 . A composition according to claim 167 in which the compound is yohimbine.
182 . A composition according to claim 167 in which the compound is usnic acid.
183 . A composition according to claim 167 in which the compound is N-{4-[2,5-Dioxo-1-(4-trifluoromethoxy-phenyl)-pyrrolidin-3-yl]-phenyl}-2,2,2-trifluoro-acetamide.
184 . A composition according to claim 167 in which the compound is a phenothiazine.
185 . A composition according to claim 167 in which the compound is a thioxanthene.
186 . A composition according to claim 167 in which the compound is a thianthrene.
187 . A composition according to claim 167 in which the compound is a phenoxazine.
188 . A composition according to claim 167 in which the compound is a phenazine.
189 . A composition according to claim 167 in which the compound is a phenoxathiin.
190 . A composition according to claim 167 in which the compound is a benzepine.
191 . A pharmaceutical composition comprising an amount of
(a) a compound having the formula (I): in which:
A is O; NR 1 ; S(O) n where n is 0, 1 or 2; CR 2 R 3 ; or —A′—CR 4 R 5 where A′ is O, NR 1 , S(O) n wherein n is 0, 1 or 2 or CR 6 R 7 , wherein R 1 through R 7 are independently hydrogen or optionally substituted aliphatic or heteroaliphatic groups;
B is N—R, O, S or CR 8 R 9 in which R is hydrogen or an optionally substituted aliphatic or heteroaliphatic group and R 8 and R 9 are independently hydrogen or optionally substituted aliphatic or heteroaliphatic groups; or when B is N—R, then R, the nitrogen atom of B, and two carbon atoms on the ring adjacent to the nitrogen atom together comprise a ring having the formula —N—C═C—C(OH)═C(COCH 3 )—C(O)—;
provided that at least one of A and B comprises an oxygen, sulfur or nitrogen ring atom;
D and E, together with the carbon atoms to which they are bonded, independently comprise optionally substituted rings of 5-7 atoms selected from C, N, S and O, wherein each ring includes at least one double bond;
and pharmaceutically acceptable salts thereof;
(b) yohimbine; (c) usnic acid; or (d) N-{4-[2,5-Dioxo-1-(4-trifluoromethoxy-phenyl)-pyrrolidin-3-yl]-phenyl}-2,2,2-trifluoro-acetamide,
that is pharmacologically effective in inhibiting a viral or microbial infection.
192 . A composition according to claim 191 in which the compound is of formula (I).
193 . A composition according to claim 193 in which D and E are unsubstituted rings.
194 . A composition according to claim 193 in which one of D and E is a mono-substituted ring.
195 . A composition according to claim 194 in which in which one of D and E is substituted by halogen, trifluoromethyl, cyano, C 1 -C 4 alkoxy or acetyl.
196 . A composition according to claim 193 in which D and E are both mono-substituted rings.
197 . A composition according to claim 191 in which the compound has the formula (II)
in which
R is hydrogen or an optionally substituted aliphatic, heteroaliphatic or cycloheteroaliphatic group, or in which the nitrogen atom, R, and two carbon atoms on the ring adjacent to the nitrogen atom, together comprise a ring having the formula —N—C═C—C(OH)═C(COCH 3 )—C(O)—;
and in which carbon atoms on the side rings of the compound are optionally substituted by one or more of —OR′, ═O, ═S, ═NR′, ═N—OR′, —NR′R″, —SR′, -halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO 2 R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O) 2 R′, —NR—C(NRR′R″)═NR′″, —R′C(NR′R″)═NR′″, —NR—C(NR′R″)═NR′″, —S(O)R′, —S(O) 2 R′, —S(O) 2 NR′R″, —NRSO 2 R′, —CN and/or —NO 2 , in which R′, R″ and R′″ are each independently selected from hydrogen, halogen, acyl, optionally substituted heteroaliphatic groups, unsubstituted aryl, aryl substituted with 1-3 halogens, optionally substituted aliphatic, optionally substituted oxyaliphatic groups, optionally substituted thioaliphatic groups, or aryl- (C 1 -C 4 )aliphatic groups;
and pharmaceutically acceptable salts thereof.
198 . A composition according to claim 197 in which both side rings are unsubstituted rings.
199 . A composition according to claim 197 in which one or both of the side rings is a mono-substituted ring.
200 . A composition according to claim 199 in which in which one of the side rings is substituted by halogen, trifluoromethyl, cyano, C 1 -C 4 alkoxy or acetyl.
201 . A composition according to claim 197 in which the side rings are both mono-substituted rings.
202 . A composition according to claim 197 in which the side rings are either unsubstituted or are substituted at the 2-position by halogen, trifluoromethyl, thiomethyl, acetyl, C 1 -C 4 alkoxy or cyano, and in which R is
(a) a C 2 -C 4 alkylene group substituted by a mono- or dialkylamino group or by an optionally substituted cycloheteroaliphatic group;
(b) an optionally substituted C 2 -C 4 unsaturated acyclic aliphatic group, or
(c) a C 2 -C 4 acyl group substituted by a mono- or dialkylamino group.
203 . A composition according to claim 197 in which the compound is acetylpromazine, chlorpromazine, prochlorperazine, promazine, or trifluoperazine.
204 . A composition according to claim 193 in which the compound has the formula (III):
in which R is (CH 2 ) 3 R 12 ; R 10 is halogen or C 1 -C 4 alkoxy; R 11 is hydrogen if R 10 is halogen and is hydrogen or methyl if R 10 is alkoxy; and R 12 is selected from —N(CH 2 CH 2 )OH, —N(n-C 4 H 9 ), —N(CH 2 C 6 H 5 ),
if R 10 is halogen, and is —N(CH 3 ) 2 if R 10 is alkoxy.
205 . A composition according to claim 191 in which the compound is yohimbine.
206 . A composition according to claim 191 in which the compound is usnic acid.
207 . A composition according to claim 191 in which the compound is N-{4-[2,5-Dioxo-1-(4-trifluoromethoxy-phenyl)-pyrrolidin-3-yl]-phenyl}-2,2,2-trifluoro-acetamide.
208 . A composition according to claim 191 in which the compound is a phenothiazine.
209 . A composition according to claim 191 in which the compound is a thioxanthene.
210 . A composition according to claim 191 in which the compound is a thianthrene.
211 . A composition according to claim 191 in which the compound is a phenoxazine.
212 . A composition according to claim 191 in which the compound is a phenazine.
213 . A composition according to claim 191 in which the compound is a phenoxathiin.
214 . A composition according to claim 191 in which the compound is a benzepine.
215 . A compound having the formula (III):
in which R is (CH 2 ) 3 R 12 ; R 10 is halogen or C 1 -C 4 alkoxy; R 11 is hydrogen if R 10 is halogen and is hydrogen or methyl if R 10 is alkoxy; and R 12 is selected from —N(CH 2 CH 2 )OH, —N(n-C 4 H 9 ), —N(CH 2 C 6 H 5 ),
if R 10 is halogen, and is —N(CH 3 ) 2 if R 10 is alkoxy.
216 . A complex formed between the TAR site of HIV RNA and
(a) a compound having the formula (I): in which:
A is O; NR 1 ; S(O) n where n is 0, 1 or 2; CR 2 R 3 ; or —A′—CR 4 R 5 where A′ is O, NR 1 , S(O) n wherein n is 0, 1 or 2 or CR 6 R 7 , wherein R 1 through R 7 are independently hydrogen or optionally substituted aliphatic or heteroaliphatic groups;
B is N—R, O, S or CR 8 R 9 in which R is hydrogen or an optionally substituted aliphatic or heteroaliphatic group and R 8 and R 9 are independently hydrogen or optionally substituted aliphatic or heteroaliphatic groups; or when B is N—R, then R, the nitrogen atom of B, and two carbon atoms on the ring adjacent to the nitrogen atom together comprise a ring having the formula —N—C═C—C(OH)═C(COCH 3 )—C(O)—;
provided that at least one of A and B comprises an oxygen, sulfur or nitrogen ring atom;
D and E, together with the carbon atoms to which they are bonded, independently comprise optionally substituted rings of 5-7 atoms selected from C, N, S and O, wherein each ring includes at least one double bond;
and pharmaceutically acceptable salts thereof;
(b) yohimbine; (c) usnic acid; or (d) N-{4-[2,5-Dioxo-1-(4-trifluoromethoxy-phenyl)-pyrrolidin-3-yl]-phenyl}-2,2,2-trifluoro-acetamide.Cited by (0)
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